Reduction of Side Effects From Aromatase Inhibitors Used for Treating Breast Cancer

ABSTRACT

The present invention is directed generally to pharmaceutical compositions, methods, and kits for improving side effects associated with aromatase inhibitor treatment in a subject diagnosed with breast cancer. More specifically, the present invention provides compositions, methods, and kits comprising an aromatase inhibitor and an androgenic agent.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the priority benefit of the followingapplications: 1) Australian Provisional Serial No. 2005905768, filed onOct. 19, 2005, 2) U.S. Provisional Ser. No. 60/732,662, filed Nov. 3,2005, and 3) U.S. Provisional Ser. No. 60/798,308, filed May 8, 2006.These applications, in their entirety, are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to the reduction of side effects caused byaromatase inhibitors which are used to treat subjects with breastcancer. In particular, the present invention provides compositions,methods, and kits for reducing side effects in post-menopausal womenwith breast cancer already being treated with aromatase inhibitorcomprising administering an effective amount of an androgenic agent.Furthermore, the present invention provides compositions, methods, andkits for reducing side effects associated with aromatase inhibitortreatment in post-menopausal women with breast cancer comprisingadministering a pharmaceutical composition comprising an aromataseinhibitor and an androgenic agent.

BACKGROUND OF THE INVENTION

Breast cancer is the most common non-cutaneous malignancy in women. Itis estimated that there were 212,600 new cases in 2003 in the USA. It isestimated that at least 13% of women will develop breast cancer at sometime in their life, and this incidence is increasing. As more than 80%of breast tumors grow in response to sex hormone stimulation caused byestrogen, part of adjuvant therapy (i.e. therapy in addition to surgicalremoval of the tumor) is to administer an agent to block this growthstimulation, including by means of blocking estrogen receptor activationor blocking estrogen production.

One such agent has been tamoxifen. Notwithstanding its success inadjuvant breast cancer therapy, tamoxifen has unwanted side-effects,which can be categorized into estrogen receptor stimulating (uterinecancer, deep venous thrombosis) and estrogen receptor antagonizing(vaginal dryness, hot flushes, mood swings) and has led to the searchfor a better alternative. A more selective estrogen receptor regulatorhas so far not been successful in taking the place of tamoxifen and thecurrent trend in hormonal therapy is to reduce the level ofbio-available estrogen.

Another such agent has been aminoglutethimide (Cash, Brough et al 1967).This drug was poorly tolerated and resulted in a marked adrenalsuppression that limited the use of the drug.

Over the past 15 years, however, more specific enzyme inhibitors havebeen developed, which specifically inhibit the aromatase enzyme thatconverts testosterone to estradiol. These compounds are known asaromatase inhibitors. They are used to block the conversion oftestosterone to estradiol, resulting in non-tissue-specific enzymaticinhibition and almost complete ablation of testosterone conversion toestradiol. The relevant conversion pathways are shown in FIG. 1.

The development of these aromatase inhibitors, such as exemestane(Aromasin®), anastrozole (Arimidex®) and letrozole (Femara®) has broughtabout a major change in the therapeutic approach to patients withhormone-sensitive breast cancer. In randomized clinical trials, each ofthese aromatase inhibitors has demonstrated efficacy in the adjuvanttreatment of post-menopausal women with receptor-positive tumors.Although long-term follow up for safety and overall survival continuesin each of these trials, currently available data suggest that anaromatase inhibitor should now be included as part of adjuvant endocrinetherapy for the great majority of receptor-positive post-menopausalpatients. The current strategy comprises at least five years of globalestrogen deprivation with a tissue non-specific aromatase inhibitor.These aromatase inhibitors overcome the significant adrenal toxicity ofthe previous anti-estrogen medications, and this has allowed them to nowbecome the most widely prescribed hormonal therapy for breast cancer.

A significant problem with these aromatase inhibitors, however, is thatthey cause unwanted and substantial short and long-term side effects.Examples of these side effects include, but are not limited to,vasodilatation, osteoporosis, osteopenia, loss of libido, weight gain,vaginal dryness, sleeping difficulties, night sweats, asthenia, painfulintercourse, pain, arthritis, arthralgia, breast pain, pharyngitis,depression, bloating, nausea, rash, mood swings, headache, diminishedcognitive function, hypertension, insomnia, lymphoedema, back pain,peripheral edema, cold sweats, abdominal pain, injury, constipation,coughing, diarrhea, fracture, hypercholesteremia, infection, arthrosis,dizziness, dyspnea, paraesthesia, urinary tract infection,vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia, flu syndrome,gastrointestinal disorder, sweating and/or leukorrhea.

The present invention described herein differs from other hormonaltherapy methods for the treatment of breast cancer. It provides theadvantages of androgen replacement therapy in combination with anaromatase inhibitor.

Current therapeutic circumstances in which an aromatase inhibitor (e.g.,Arimidex®) and an androgenic agent (e.g., testosterone) have been usedin combination previously are to reduce the estrogenic effect oftestosterone abuse in body building, in particular gynaecomastia(Hoffmann J Raatamess N Journal of Sports Science and Medicine 5,182-183 (2006), to reduce estrogenic side-effects in hypogonadal men onT therapy (Leder et al. 2004, and Leder et al. 2005), and to explore thesafety issues (risk of cardiovascular disease) of androgen replacementtherapy, specifically in female to male transexuals undergoingtestosterone therapy. (Bunck et al. 2006). None of these circumstancesof androgen replacement therapy, however, were for the treatment of awoman diagnosed with breast cancer. In fact, there has been a greatreluctance by the medical profession to prescribe hormone substrates towomen who have hormonally active breast cancers. The use of androgenreplacement is controversial in post-menopausal women generally, and itsuse in women who have had breast cancer is almost universallycontra-indicated. For example, a Proctor & Gamble application to the FDAfor the Intrinsa product cited breast cancer as an absolutecontra-indication to using the Intrinsa patch because of the concernabout the testosterone being converted to estradiol and being used as agrowth substrate by the malignancy (Shifren J L et al Testosterone patchfor the treatment of hypoactive sexual desire disorder in naturallymenopausal women: results from the INTIMATE NM1 study Menopause (inpress).

Regardless of such medication, the conventional understanding remainsthat androgen (e.g., testosterone) replacement should be avoided inbreast cancer subjects for fear of spurring tumor regrowth.

The present invention, however, goes against this conventional wisdom ofnot prescribing androgenic agents to women diagnosed with breast cancer.The present invention provides a novel therapy to alleviate side-effectsof and/or to enhance the efficacy of aromatase inhibitor therapy inbreast cancer treatment by supplementing and/or combining an aromataseinhibitor with an androgenic agent.

SUMMARY OF THE INVENTION

The present invention is directed generally to pharmaceuticalcompositions, methods, and kits for improving side effects associatedwith aromatase inhibitor treatment in a subject diagnosed with breastcancer.

One aspect of the present invention provides a pharmaceuticalcomposition for improving a side effect associated with aromataseinhibitor treatment in a subject diagnosed with breast cancer comprising(a) an effective amount of an androgenic agent and (b) an effectiveamount of an aromatase inhibitor. Optionally, the pharmaceuticalcomposition may comprise a pharmaceutically acceptable excipient and/orcarrier.

Another aspect of the present invention provides a pharmaceuticalcomposition for improving one or more side effects associated witharomatase inhibitor treatment in a subject diagnosed with breast cancercomprising an effective amount of an androgenic agent, and optionally apharmaceutically acceptable excipient and/or carrier.

A further aspect of the present invention is a method for improving oneor more side effects associated with aromatase inhibitor treatment in asubject diagnosed with breast cancer comprising administering to asubject a pharmaceutical composition comprising (a) an effective amountof an androgenic agent and (b) an effective amount of an aromataseinhibitor, and, optionally, a pharmaceutically acceptable excipientand/or carrier.

Another aspect of the present invention is a method for improving one ormore side effects associated with aromatase inhibitor treatment in asubject diagnosed with breast cancer comprising administering to asubject a pharmaceutical composition comprising an effective amount ofan androgenic agent and, optionally, a pharmaceutically acceptableexcipient and/or carrier.

An additional aspect of the present invention is a method for improvingthe health of a subject with breast cancer having one or more sideeffects associated with aromatase inhibitor therapy comprisingadministering a pharmaceutical comprising an effective amount of anandrogenic agent, and, optionally, a pharmaceutically acceptableexcipient and/or carrier; or an effective amount of an androgenic agent,an effective amount of an aromatase inhibitor, and, optionally, apharmaceutically acceptable excipient and/or carrier.

Another aspect of the present invention provides methods ofmanufacturing pharmaceutical compositions for improving one or more sideeffects associated with aromatase inhibitor treatment in a subjectdiagnosed with breast cancer comprising selecting an androgenic agent.

Furthermore, an aspect of the present invention is a kit for improvingone or more side effects associated with aromatase inhibitor treatmentin a subject diagnosed with breast cancer comprising an androgenicagent, an aromatase inhibitor, and instructions.

Another aspect of the present invention is a method for enhancing theefficacy of aromatase inhibitors comprising administering apharmaceutical composition of the present invention

Another aspect of the present invention is a method for increasing thebioavailability of an androgenic agent comprising administering apharmaceutical composition of the present invention.

One aspect of the present invention provides a pharmaceuticalcomposition for improving a side effect associated with an aromataseinhibitor such as third generation aromatase inhibitor treatment in asubject diagnosed with breast cancer comprising (a) an effective amountof an androgenic agent and (b) an effective amount of a such thirdgeneration aromatase inhibitor. Optionally, the pharmaceuticalcomposition may comprise a pharmaceutically acceptable excipient and/orcarrier.

A further aspect of the present invention is a method for improving oneor more side effects associated with an aromatase inhibitor such asthird generation aromatase inhibitor treatment in a subject diagnosedwith breast cancer comprising administering to a subject apharmaceutical composition comprising (a) an effective amount of anandrogenic agent and (b) an effective amount of a third generationaromatase inhibitor, and, optionally, a pharmaceutically acceptableexcipient and/or carrier.

An additional aspect of the present invention is a method for improvingthe health of a subject with breast cancer having one or more sideeffects associated with an aromatase inhibitor such as third generationaromatase inhibitor therapy comprising administering a pharmaceuticalcomprising an effective amount of an androgenic agent, and, optionally,a pharmaceutically acceptable excipient and/or carrier; or an effectiveamount of an androgenic agent, an effective amount of a third generationaromatase inhibitor, and, optionally, a pharmaceutically acceptableexcipient and/or carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing aspects and advantages of the present invention will bereadily apparent to one skilled in the art upon reference to the figuresand the detailed description which follows.

FIG. 1 is a schematic diagram depicting various biological steroidreaction pathways.

FIG. 2 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and an androgenic agent (testosteroneundecanoate) upon serum hormone levels in post-menopausal patientsreferred to in the example described herein.

FIG. 3 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and an androgenic agent (testosteroneundecanoate) upon serum markers for bone resorption in post-menopausalpatients referred to in the example described herein.

FIG. 4 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and an androgenic agent (testosteroneundecanoate) as measured by arthralgia evaluations in post-menopausalpatients referred to in the example described herein.

FIG. 5 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and an androgenic agent (testosteroneundecanoate) as measured by FACT-ES side-effect profile evaluations inpost-menopausal patients referred to in the example described herein.

FIG. 6 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and androgenic agent (testosteroneundecanoate) as measured by cognitive function evaluations inpost-menopausal patients referred to in the example described herein.

FIG. 7 is a chart demonstrating the effects of a combination of anaromatase inhibitor (Arimidex®) and an androgenic agent (testosteroneundecanoate) upon serum lipid levels in post-menopausal patientsreferred to in the example described herein.

FIG. 8 is a questionnaire of the endocrine subscale for the FACT-B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

Terms are used herein as generally used in the art, unless otherwisedefined in the following:

The term “a” or “an” refers to one or more of the described entity; forexample, “an aromatase inhibitor” is understood to represent one or morearomatase inhibitors. Another example is “an androgenic agent” isunderstood to represent one or more androgenic agents. Another exampleis “for improving a side effect” is understood to include improving oneor more side effects. As such, the terms “a” (or “an”), “one or more,”and “at least one” can be used interchangeably herein.

The term “about” as used herein may be applied to modify anyquantitative representation that could permissively vary withoutresulting in a change in the basic function to which it is related.

“Adjuvant therapy” may include adjuvant, neo-adjuvant and/or palliativetherapy.

“Androgenic agent” refers to a chemical that increases androgenicactivity or synthesis. Typically, an androgenic agent is a steroidhormone that binds with high affinity (in the pM or nM range) andspecificity to its intracellular mediator, the androgen receptor, tostimulate transactivation activity and thus regulate the expression oftarget genes. Examples are provided herein.

“Aromatase inhibitor” refers to a chemical compound or polypeptide thatblocks or inhibits the activity of aromatase which is an enzyme thatconverts androgens to estrogens. Examples are provided herein.

“Breast cancer” refers to a malignant proliferation of epithelial cellslining the ducts or lobules of the breast.

“Collagen crosslink” refers to a pyridinoline and deoxy-pyridinolinecrosslink.

“Diagnosed” is meant to include a subject suspected or predicted to havebreast cancer.

“Effective amount” or “pharmaceutically effective amount” of an agent orcompound as provided herein refers to a nontoxic but sufficient amountof the agent or compound to provide the desired therapeutic effect. Aswill be pointed out below, the exact amount required will vary fromsubject to subject, depending on age, general condition of the subject,the severity of the condition being treated, and the particular agent orcompound administered, and the like. An appropriate “effective amount”in any individual case may be determined by one of ordinary skill in theart by reference to the pertinent texts and literature and/or usingroutine experimentation.

“Improving one or more side effects” includes, but is not limited to,the prevention, treatment, reversal, part-reversal, reduction,diminution, or amelioration of a side effect.

“Improving the health of a subject” includes, but is not limited to,improving one or more side effects and/or improving the therapeuticeffect of the aromatase inhibitor.

“Pharmaceutically acceptable” refers to those compounds, agents,materials, compositions, excipients, and/or dosage forms that are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complicationscommensurate with a reasonable benefit/risk ratio.

“Post-menopausal woman” is defined to include not only a woman ofadvanced age who has passed through menopause, but also a woman who hasbeen hysterectomized or for some other reason has suppressed estrogenproduction, such as one who has undergone long-term administration ofcorticosteroids, suffer from Cushions' syndrome or have gonadaldysgenesis.

“Side effect” refers to a consequence other than the one(s) for which anagent or measure is used, as the adverse effects produced by a drug,especially on a tissue or organ system other then the one sought to bebenefited by its administration. Examples are providing herein.

“Subject” is an animal including the human species that is treatablewith the compositions, methods and kits of the present invention. Theterm “subject” or “subjects” is intended to refer to both the male andfemale gender unless one gender is specifically indicated.

The term “treatment” or “therapy” as used herein includes preventative(e.g., prophylactic) and palliative treatment and “treating” as usedherein refers to the act of providing preventative and/or palliativetreatment.

It will be apparent to one skilled in the art, in view of the followingdetailed description and the claims appended hereto, that varioussubstitutions and/or modifications may be made to the present inventionwithout departing from the scope of the invention as claimed.

Pharmaceutical Compositions

A pharmaceutical composition for improving one or more side effectsassociated with aromatase inhibitor treatment in a subject with breastcancer, comprising (a) an effective amount of androgenic agent, andoptionally (b) a pharmaceutically acceptable excipient and/or carrier iswithin the scope of the present invention. Furthermore, a pharmaceuticalcomposition for improving one or more side effects associated witharomatase inhibitor treatment in a subject with breast cancer comprising(a) an effective amount of androgenic agent, (b) an effective amount ofan aromatase inhibitor, and optionally (c) a pharmaceutically acceptableexcipient and/or carrier is within the scope of the present invention.

An androgenic agent of the present invention can, for example, beselected from the group consisting of: testosterone, methyltestosterone, testosterone undecanoate, testosteronepropionatedihydrotestosterone, 5α-dihydrotestosterone, or alternativelyandrostenediol androstenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione, adrenosterone,androsterone acetate, androsterone propionate, androsterone benzoate,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,oxymetholone, fluoxymesterone, methandrostenolone, testolactone,pregnenolone, 17α-methylnortestosterone, norethandrolone,dromostanolone, dromostanolone propionate, nandrolone, nandrolonephenpropionate, nandrolone decanoate, nandrolone furylpropionate,nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, danazol, oxymetholone, androsterone, stanozolol,ethylestrenol, oxandrolone, bolasterone, mesterolone, testosteronecypionate, testosterone phenylacetate, testosterone enanthate,testosterone acetate, testosterone buciclate, testosterone heptanoate,testosterone decanoate, testosterone caprate, testosterone isocaprate,and isomers, metabolites, derivatives, and precursors of any of theaforementioned compounds, and combinations thereof. In addition to thepharmaceutically acceptable esters of testosterone, esters ofdihydrotestosterone, include, but are not limited to, the enanthate,propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate,heptanoate, decanoate, undecanoate, caprate and isocaprate esters. Theaforementioned esters are commercially available or may be readilyprepared using techniques known to those skilled in the art or describedin the pertinent literature.

The aforementioned androgenic agents are selected from the groupconsisting of naturally occurring androgens, synthetic androgens,metabolites, precursors, and derivatives thereof. The agents may beincorporated into the present dosage units and thus administered in theform of a pharmaceutically acceptable derivative, metabolite, precursor,analog, ester, salt, or amide, or the agents may be modified byappending one or more appropriate functionalities to enhance selectedbiological properties such as penetration through mucosal tissue. Ingeneral, with regard to androgenic agents, esters are preferred relativeto salts or other derivatives.

Preparation of esters, as noted in the preceding section, involvesfunctionalization of hydroxyl and/or carboxyl groups that may bepresent, as will be appreciated by those skilled in the arts ofpharmaceutical chemistry and drug delivery. For example, to preparetestosterone esters, the 17-hydroxyl group of the testosterone moleculeis generally caused to react with a suitable organic acid underesterifying conditions, such conditions typically involving the use of astrong acid such as sulfuric acid, hydrochloric acid, or the like, and atemperature sufficient to allow the reaction to proceed at reflux.Esters can be reconverted to the free acids, if desired, by usingconventional hydrogenolysis or hydrolysis procedures.

Preferably, the androgenic agent of the present invention istestosterone, methyltestosterone, testosterone undecanoate, testosteronepropionate, dehydroepiandrosterone, or sodium dehydroepiandrosteronesulfate, or a metabolic precursor, metabolite, or derivative thereof.More preferably, the androgenic agent of the present invention istestosterone, methyltestosterone, testosterone undecanoate, ortestosterone propionate, or a metabolic precursor, metabolite, orderivative thereof. Most preferably, the androgenic agent is provided inthe form of testosterone undecanoate, an orally active testosteronepreparation that is a fatty acid ester of the natural androgentestosterone. Unlike other oral testosterone preparations, testosteroneundecanoate is able to by-pass the liver via the lymphatic system and istherefore orally bioavailable.

Additionally, testosterone is difficult to deliver orally, as 80-90% isbroken down in the liver as it is absorbed from the gut. As such,alternate delivery mechanisms have been explored, e.g. theaforementioned testosterone patch (Intrinsa®) by Proctor & Gamble usedto improve sexual libido in post-menopausal women because of theprogressive decline in testosterone levels with age and in women whohave their ovaries removed.

An effective amount of an androgenic agent may vary among eachandrogenic agent. For example, an effective amount per day oftestosterone may vary. In one embodiment, an effective amount oftestosterone may be between about 2 to about 80 mg, between about 5 toabout 75 mg, between about 10 to about 70 mg, between about 20 to about60 mg, between about 30 to about 50 mg, and between about 35 to about 45mg. In another embodiment, a preferred amount is about 20 mg. In oneembodiment, a preferred amount is about 40 mg. In one embodiment, apreferred amount is about 50 mg.

An effective amount per day of methyltestosterone may vary. In oneembodiment, an effective amount of methyltestosterone may be betweenabout 0.1 mg to about 10 mg, between about 0.5 mg to about 9 mg, betweenabout 1 mg to about 9 mg, between about 2 mg to about 8 mg, betweenabout 3 mg to about 7 mg, and between about 4 mg to 5 mg. In oneembodiment, a preferred. amount is about 0.5 mg. In another embodiment,a preferred amount is about 1.25 mg. In one embodiment, a preferredamount is about 2.5 mg.

An effective amount per day of testosterone undecanoate may vary. Insome embodiments, an effective amount of testosterone undecanoate may bebetween about 10 to about 120 mg, between about 20 to about 110 mg,between about 30 to about 100 mg, between about 40 to about 90 mg,between about 50 to about 80 mg, and between about 60 to about 70 mg. Inone embodiment, a preferred amount is about 20 mg. In anotherembodiment, a preferred amount is about 40 mg. In one embodiment, apreferred amount is about 80 mg.

An effective amount per day of testosterone propionate may vary. In someembodiments, an effective amount of testosterone propionate may bebetween about 10 to about 120 mg, between about 20 to about 110 mg,between about 30 to about 100 mg, between about 40 to about 90 mg,between about 50 to about 80 mg, and between about 60 to about 70 mg. Inone embodiment, a preferred amount is about 20 mg. In anotherembodiment, a preferred amount is about 40 mg. In one embodiment, apreferred amount is about 80 mg.

The effective amount of androgenic agent used in conjunction with anaromatase inhibitor is relatively lower than a standard dose because oflow levels of sex hormone binding globulin which may be caused by thearomatase inhibitor.

Sex hormone binding globulin binds an androgenic agent (e.g.,testosterone) and transports it around the body. Its production isregulated by several mechanisms, but one of the most profound effectorsof its level is the amount of estrogen in the serum: the higher theestrogen, the higher the sex hormone binding globulin and the lower thefree androgenic agent. Conversely, the lower the estrogen, the lower thesex hormone binding globulin, and the higher the free androgenic agent,which means the androgenic agent is has higher bioavailability. Thusafter menopause, as the estrogen level falls, the sex hormone bindingglobulin level falls and the free androgenic agent such as testosteronerises. This free androgenic agent has multiple functions, as theandrogen receptor is expressed in all cells of the body.

In some instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesabove the upper limit of the aforesaid range may be employed withoutcausing any harmful side effects.

An aromatase inhibitor of the present invention, for example, can beselected from the group consisting of either steroidal or nonsteroidalaromatase inhibitors, and/or isomers thereof. Steroidal aromataseinhibitors developed to date build upon the basic androstenedionenucleus and incorporate chemical substituents at varying positions onthe steroid. Examples of steroidal aromatase inhibitors include, but arenot limited to, exemestane (Aromasin®) and formestane. Additionalexamples include mechanism-based steroidal aromatase inhibitors thatmimic the substrate, are converted by the enzyme to a reactiveintermediate, and result in the inactivation of aromatase. Preferably,an aromatase inhibitor of the present invention is exemestane.

Nonsteroidal aromatase inhibitors can be divided into three classes:aminoglutethimide-like molecules, imidazole/triazole derivatives, andflavonoid analogs. Examples of non-steroidal aromatase inhibitorsinclude, but are not limited to, anastrozole (Arimidex®), letrozole(Femara®), vorozole and fadrozole. Preferably, an aromatase inhibitor ofthe present invention is either anastrozole or letrozole.

Aromatase inhibitors often include third-generation aromataseinhibitors, such as anastrozole (Arimidex®), exemestane (Aromasin®), andletrozole (Femara®). These third generation aromatase inhibitors havebrought about a major change in the therapeutic approach to patientswith hormone-sensitive breast cancer. Such aromatase inhibitors are veryspecific in their action in that they virtually ablate estrogen in theserum and thus lower sex hormone binding globulin, which enables theachievement of a synergistic effect in embodiments of the invention.

An effective amount of an aromatase inhibitor may vary among eacharomatase inhibitor. For example, an effective amount per day forAromasin® may vary. In some embodiments, an effective amount may bebetween about 5 to about 100 mg, between about 10 to about 80 mg,between about 20 to about 70 mg, between about 30 to about 60 mg, andbetween about 40 to about 50 mg. Also, in some embodiments, an effectiveamount may be between about 25 to about 100 mg and between about 35 toabout 100 mg. Furthermore, in some embodiments, an effective amount maybe between about 25 to about 150 mg, about 50 to about 150 mg, and about80 to about 150 mg. In one embodiment, a preferred amount is about 25mg.

An effective amount per day of Arimidex® may vary. In some embodiments,an effective amount for Arimidex® may be between about 0.1 mg to about 5mg, between about 0.5 mg to about 4 mg, between about 1 mg to about 3mg, and between about 1.5 mg to about 2.5 mg. Also, in some embodiments,an effective amount may be between about 1 mg to about 5 mg and betweenabout 1.5 mg to about 5 mg. Furthermore, in some embodiments, aneffective amount may be between about 1 mg to about 7.5 mg, betweenabout 1 mg to about 10 mg, and between about 1 mg to about 20 mg. In oneembodiment, a preferred amount is about 1 mg.

An effective amount per day of Femara® may vary. In some embodiments, aneffective amount may be between about 1 to about 5 mg, between about 1.5to 4 mg, between about 2 to about 3.5 mg, and between about 2.5 to about3 mg. Also, in some embodiments, an effective amount may be betweenabout 2.5 mg to about 5 mg and between about 3.5 mg to about 5 mg.Furthermore, in some embodiments, an effective amount may be betweenabout 2.5 mg to about 7.5 mg, between about 2.5 mg to about 10 mg, andbetween about 2.5 mg to about 20 mg. In one embodiment, a preferredamount is about 2.5 mg.

In some instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesabove the upper limit of the aforesaid range may be employed withoutcausing any harmful side effects. For example, dosages of an aromataseinhibitor above the upper limit may be used to improve thebioavailability of an androgenic agent such as testosterone ordihydrotestosterone, as described below.

Testosterone naturally is not highly absorbed because it is broken downapproximately 85% in the intestines by aromatase and other metabolicpathways into by-products such as inactive testosterone anddihydrotestosterone. The administration of an aromatase inhibitor incombination with testosterone, however, results in an increasedabsorption, and subsequently greater bioavailability.

In one embodiment of the invention, the administration of an aromataseinhibitor in combination with testosterone results in an improvement inthe bioavailability of testosterone between about 10% to about 50%,between about 20% to about 40%, and between about 25% to about 35%. Apreferred amount of increase in bioavailability is greater than about15%, greater than about 25%, greater than about 30%, or greater thanabout 35%.

In another embodiment of the invention, the administration of aromataseinhibitor in combination with testosterone results in an improvement inthe bioavailability of dihydrotestosterone between about 25% to about75%, between 35% to about 65%, and between 45% to 55%. A preferredamount of increase in dihydrotestosterone bioavailability is greaterthan about 25%, greater than about 35%, greater than about 45, orgreater than about 55%.

An embodiment of the invention includes a pharmaceutical compositioncomprising an androgenic agent and an aromatase inhibitor. A preferredembodiment is a pharmaceutical composition comprising a testosterone. Aspecific embodiment consists of testosterone undecanoate. An additionalembodiment consists of about 40 mg of testosterone undecanoate.

Another embodiment of the invention includes a pharmaceuticalcomposition comprising an androgenic agent and an aromatase inhibitorselected from the group consisting of exemestane, formestane,anastrozole, letrozole, vorozole, or fadrozole. A preferred embodimentconsists of anastrozole. A specific embodiment consists of about 1 mg ofanastrozole.

A specific embodiment taught by the invention consists of apharmaceutical composition comprising testosterone undecanoate andanastrozole. More specifically, this embodiment comprises about 40 mg oftestosterone undecanoate and about 1 mg of anastrozole.

An alternative embodiment of the invention includes a pharmaceuticalcomposition comprising an androgenic agent.

An alternative embodiment of the invention includes a pharmaceuticalcomposition comprising an androgenic agent linked to an aromataseinhibitor, e.g., via an ester linkage.

Another alternative embodiment of the invention includes apharmaceutical composition comprising an androgenic agent/aromataseinhibitor complex, wherein the complex is created by known methods inthe art.

Methods of Administering the Pharmaceutical Compositions of the PresentInvention

A method of administering a pharmaceutical composition of the presentinvention to improve one or more side effects associated with aromataseinhibitor treatment in a subject with breast cancer is within the scopeof the present invention.

Pharmaceutical compositions of this invention can be administered by anyroute compatible with a desired outcome. Thus, routes of administrationinclude orally (e.g., ingestion or inhalation), intraperitoneally,intradermally, transdermally, transmucosally, subcutaneously,sublingually, intravenously, intraarterially, intracavity,intracranially, intramuscularly, parenterally, or topically. Preferably,the aromatase inhibitor and the androgenic agent are administered orallyor transdermally.

The pharmaceutically acceptable agents are administered alone or incombination with pharmaceutically acceptable carriers, excipients, ordiluents, and such administration may be carried out in single ormultiple doses. More particularly, the therapeutic agents of thisinvention can be administered in a wide variety of different dosageforms, i.e., they may be combined with various pharmaceuticallyacceptable inert carriers or excipients in the form of tablets,capsules, emulsions, lozenges, troches, hard candies, lollipops,powders, sprays, creams, salves, suppositories, jellies, gels, pastes,lotions, ointments, aqueous suspensions, injectable solutions, elixirs,syrups, injectable depots, implants, microencapsulated delivery systems,oil-based suspensions, and the like.

For example, androgenic agents may be administered by the aforementionedroutes and dosage forms. In one embodiment, testosterone esters may beinjected. These may include testosterone enanthate (Delatestryl) whichis suspended in sesame oil, testosterone cypionate (Depo-Testosterone)which is suspended in cottonseed oil, testosterone propionate (Testovis;Virormone), testosterone phenylpropionate (Testolent), and a blend offour testosterone esters (Sustanon; Omnadren) which include testosteronepropionate, testosterone phenylpropionate, testosterone isocaproate, andtestosterone decanoate.

In another embodiment, testosterone may be injected as an aqueoussuspension (Aquaviron).

In another embodiment, testosterone may be administered via atransdermal patch (Androderm; Testoderm TTS).

In another embodiment, testosterone may be administered by a gel(Androgel; Testim).

In another embodiment, methyltestosterone may be administered orally,e.g., tablet. (Metesto, Methitest, Testred, Oreton Methyl, and Android).

In another embodiment, testosterone undecanoate may be administeredorally, e.g., tablet (Androxon, Understor, Restandol, and Restinsol).

In one embodiment, testosterone may be administered buccally (Striant).

In another embodiment, testosterone may be administered subcutaneously,e.g., pellet (Testopel).

The instant pharmaceutical combinations comprising an aromataseinhibitor of the invention in combination with an androgenic agentinclude administration of a single pharmaceutical dosage formulationwhich contains both substances, as well as administration of each agentin its own separate pharmaceutical dosage formulation.

It is well known that patient compliance is a factor in receiving a goodresult in medical treatment. Causes for poor compliance may include, butare not limited to, complicated regimen, unattractive and/or painfulformulation such as needles, and physical difficulty in complying.Therefore, administration of two or even more different dosage forms tothe patient may not be convenient or satisfactory to achieve the mostoptimal results. A pharmaceutical composition of the present inventioncomprising an androgenic agent and aromatase inhibitor combined into asingle dosage form may provide improved patient compliance.

Where separate dosage formulations are used, the aromatase inhibitor andthe androgenic agent can be administered at essentially the same time,i.e., concurrently, or at separately staggered times, i.e.,sequentially. The pharmaceutical compositions of the present inventionis understood to include all these regimens. Administration of thepharmaceutical composition by any routes mentioned above using any ofthese regimens is suitable for the present invention as long as thebeneficial pharmaceutical effect of the aromatase inhibitor andandrogenic agent are realized by the patient. It is preferred that thearomatase inhibitor and androgenic agent be administered concurrently ona once-a-day dosing schedule; however, varying dosing schedules, such asthe aromatase inhibitor once per day and the androgenic agent once,twice or more times per day, or the androgenic agent once per day andthe aromatase inhibitor once, twice or more times per day, is alsoencompassed herein. A single oral daily dosage formulation comprised ofboth the aromatase inhibitor and androgenic agent is preferred. A singledosage formulation will provide convenience for the subject.

The appropriate dosing regimen utilizing the pharmaceuticalcompositions, the amount of each dose administered, and the intervalsbetween doses of the compounds according to the present invention willdepend on various factors such as the particular aromatase inhibitor andandrogenic agent being used in combination, the type of pharmaceuticalformulation being used, the type of physiological condition beingtreated, the characteristics of the subject being treated (e.g.,species, age, weight, sex, medical condition, fed/fasted), the route ofadministration, and the severity of the disorder being treated. Aphysician or veterinarian of ordinary skill can readily determine andprescribed the effective amount of the pharmaceutical composition toprevent or to treat the specific physiological condition.

Such compositions may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses several timesdaily. Furthermore, the pharmaceutical compositions may be administeredas a single dose or over a period of time. Additionally, thepharmaceutical composition can be administered continuously orintermittently. The daily dosage may be varied over wide range and canbe such that the amount of the active compound selected from theandrogenic agent and/or aromatase inhibitor is sufficient to cause itsdesired effects.

The pharmaceutical compositions of the present invention areadministered to a subject diagnosed with breast cancer, preferably aperimenopausal or a postmenopausal woman.

The duration of treatment for administration of the pharmaceuticalcompositions of the present invention may vary between about threemonths to about ten years, between about four months to about fiveyears, and between about six months to about four years. A preferredduration of treatment is about six months. Another preferred duration oftreatment is about five years.

The composition or formulation to be administered will contain aquantity of the compounds or pharmaceutically acceptable salts thereofof the invention in an amount effective to treat the disease/conditionof the subject being treated. Because two different compounds are beingused together in a combination therapy, the potency of each of thecompounds and the interactive effects achieved by combining themtogether must also be taken into account. A consideration of thesefactors is well within the purview of the ordinarily skilled clinicianfor the purpose of determining the therapeutically effective orprophylactically effective dosage amounts needed to improve sideeffects.

Administration, of the pharmaceutical composition to the subjectincludes both self-administration and administration to the subject byanother person (e.g., physician, health care worker, friend).

An embodiment of the present invention includes a method for improvingone or more side effects associated with aromatase inhibitor treatmentin a subject diagnosed with breast cancer comprising administering apharmaceutical composition, as described previously, to a subject orallyor transdermally. A specific embodiment includes a method ofadministering a solid oral dosage form (e.g., tablet) once a day.

Another embodiment of the present invention involves a method ofadministering pharmaceutical compositions, described above, as adjuvant,neo-adjuvant or palliative therapy to a subject with breast cancer whohas already received chemotherapy.

An additional embodiment of the present invention involves a method ofincreasing the absorption rate of an androgenic agent in a subjectdiagnosed with breast cancer comprising administering pharmaceuticalcompositions described within the specification. A specific embodimentof the present invention includes increasing the absorption rate oftestosterone orally if conversion of estrogen is blocked in small bowelmucosa, submucosa, microvessels, lymphatics and liver by an aromataseinhibitor. As aromatase is a major enzyme in the small bowel and liver,specific high efficiency aromatase inhibitors will reduce testosteronemetabolism on oral intake.

Measuring Side Effects Associated with Aromatase Inhibitor Treatment

A method for measuring side effects associated with aromatase inhibitortreatment is within the scope of the present invention.

Both steroidal and non-steroidal aromatase inhibitors have shownclinical efficacy in the treatment of breast cancer. Recently, theAmerican Society of Oncology has recommended that aromatase inhibitor beused as adjuvant therapy in all post-menopausal women with hormonallysensitive early breast cancer. This raises significant problems with themanagement of side-effects caused by total estrogen deprivation forperiods of between five and ten years. Currently, the duration ofhormonal adjuvant therapy is five years. However, this concept is beingchallenged, which may result in a longer duration of estrogendeprivation (Baum 2005). Most of the side-effects of aromataseinhibitors can be attributed to estrogen deprivation in specifictissues, but some are difficult to categorize. An example is loss oflibido, which may have several synergistic etiologies, but appears to besignificantly higher in Al than in TAM usage (Fallowfield, Cella et al2004). However, there is little doubt that the musculoskeletalside-effects, such as arthralgia and osteoporosis, are a direct resultof estrogen deprivation in these tissues and are a frequent occurrencein aromatase inhibitor users (Ingle 2005). Bone fractures duringaromatase inhibitor therapy may be increased by as much as 60%, and thisis probably a result of increased bone turnover (up by 20%), as well asaccelerated bone loss (Eastell and Hannon 2005). The long-termside-effects of aromatase inhibitors are not known but are of concern,especially in the area of cognition (Jenkins, Shilling et al 2004),where estrogen is known to be especially important (reviewed in Sherwin2003). There appears to be a critical window in the peri-menopausalperiod in which hormone levels may be critical to cognitive function(Sherwin 2003).

Administration of an androgenic agent simultaneously in combination withan aromatase inhibitor or following the administration of an aromataseinhibitor serves to improve one or more side effects associated witharomatase inhibitor administration, such as hot flush, hot flash,vasodilatation, osteoporosis, osteopenia, loss of libido, weight gain,vaginal dryness, sleeping difficulties, night sweats, asthenia, painfulintercourse, pain, whole body pain, arthritis, arthralgia, breast pain,pharyngitis, depression, bloating, nausea, rash, mood swings, headache,diminished cognitive function, hypertension, insomnia, lymphoedema, backpain, peripheral edema, cold sweats, abdominal pain, injury,constipation, coughing, diarrhea, fracture, hypercholesteremia,dyslipidemia, infection, arthrosis, dizziness, dyspnea, paraesthesia,urinary tract infection, vulvovaginitis, anxiety, bone pain, chest pain,dyspepsia, flu syndrome, gastrointestinal disorder, sweating and/orleukorrhea. Preferably, administration of an androgenic agentsimultaneously in combination with an aromatase inhibitor or followingthe administration of an aromatase inhibitor serves to improve one ormore side effects associated with aromatase inhibitor administration,such as hot flush, hot flash, vasodilatation, osteoporosis, osteopenia,night sweats, whole body pain, arthritis, arthralgia, pain, diminishedcognitive function, and arthrosis.

One embodiment of the present invention involves measuring serum, urine,and/or fecal levels of markers for bone resorption. Such markers of boneresorption include, but are not limited to, carboxy-terminal collagencrosslinks (pyridinoline, deoxypryridinoline) N-telopeptide,hydroxyproline, tartrate-resistant acid phosphatases, and galactosylhydroxylysine. Also, markers for bone formation such as osteocalcin maybe measured. Another measurement of bone resorption/bone formation arechanges in calcium and phosphorus balances (positive or negative) whichare determined by measuring the difference between the total excretion(feces and urine) and the dietary intake of calcium or phosphorus ion.(These balances are positive when the total excretion is less than thedietary intake.) Preferably, serum levels of-carboxy-terminal crosslinksare measured.

Another embodiment of the present invention involves measuring thequality of life caused by estrogen deprivation. There are endocrinetherapies for use with women who have breast cancer. Several clinicaltrials of adjuvant therapy comparing different drugs with the aim ofdetermining efficacy, toxicity and overall general health and well-beingare in progress or have recently reported. Publications containing thesystematic collection of comprehensive subjective data to date are fewthus little is known about the impact that hormone therapy exert on thequality of women's lives. The side-effects of some endocrine therapiesmay be underestimated by healthcare professionals when their views arecompared with those of patients. However the side-effects of differenttreatments and the impact that these may have on quality of life (QOL)must be determined if informed choices about disease management are tobe made. For example, menopausal symptoms may be considered too high aprice for some women to pay in adjuvant therapy, especially if suchtreatment is still of unknown benefit in terms of preventing recurrenceof the disease. Furthermore, without an assessment of quality of life,it is difficult to know what supportive and ameliorative interventionsmay be needed to accompany the treatment found to be most efficacious interms of treating breast cancer and preventing its recurrence. Themagnitude of difference between treatment groups that may be expected interms of QOL and the incidence of symptoms is likely to be larger thanthe differences in survival.

There are several quality of life instruments or assessments that canused to assess the impact that hormone treatment (and the inventionsdisclosed herein) have on different aspects of a person's functioningand well being. Other ways of measuring or assessing the side effectsassociated with the inventions disclosed herein are available and willbe known to those of skilled in the art and, if appropriate, may beused.

An endocrine subscale (FACT-ES) to accompany a well-validated QOLmeasure called the FACT-B (Brady, M J., et al., Journal of Clinical.Oncology., Vol. 15, No. 3 (March 1997) pp. 974-986, which isincorporated in its entirety) was developed specifically for use intrials using drugs likely to cause endocrine related symptoms. SeeFallowfield, L J, et al., Breast Cancer Research and Treatment, Vol. 55,No. 2, 1999, pp. 189-199, which is incorporated herein by reference inits entirety. Also, FACT-ES is a validated questionnaire designed tomeasure quality of life of women with breast cancer who are beingtreated with endocrine therapies. It consists of the FACT-Bquestionnaire plus an additional endocrine subscale. FACT-B (breast)consists of the FACT-G (general) QOL tool for cancer patients plus theBreast Cancer subscale. FACT-ES has been developed to measure QOL inpatients receiving endocrine therapy for breast cancer. This instrument(FACT-ES) should, therefore, be sensitive to QOL changes in patients inthis trial. The FACT-B (version 4)is a multi-dimensional self-reportquestionnaire measuring five domains: physical well-being, socialwell-being, emotional well-being, functional well-being, and breastcancer concerns. It has good psychometric properties, discriminates wellbetween groups and is responsive to change. It is relatively simple andquick to complete, has been translated into many different languages andis being used in a large number of breast trials in the US and Europe.This sub-protocol will assess the QOL in all consenting patients overthis period and at recurrence, should this occur within the studyperiod.

Another preferred embodiment of the present invention involves measuringjoint pain using the visual numeric scoring (VNS) on the AmericanCollege of Rheumatology scoring system. The Western Ontario and McMasterUniversities (WOMAC) Osteoarthritis Index™ consists of three VAS, oneeach pertaining to pain, joint stiffness and physical function. Thisthen gives the WOMAC™ osteoarthritis index composite score. (See BellamyN. J Rheum 15:1833-1840, 1988, incorporated herein by reference in itsentirety).

Another embodiment of this invention involves measuring cognitivefunction, including processing speed, working memory, visual memory, andverbal memory. The improvement of one or more side effects associatedwith aromatase inhibitor treatment in a subject diagnosed with breastcancer may be measured by the following (Fallowfied Assessment. (SeeJenkins V. Psychooncology 13:61-66, 2004, incorporated herein byreference in its entirety).

A further embodiment of this invention involves measuring serum lipids,including, but not limited to, cholesterol, HDL, and LDL.

Manufacturing the Pharmaceutical Compositions of the Present Invention

A method for manufacturing a pharmaceutical composition of the presentinvention and any articles of manufacture produced thereof are withinthe scope of the present invention.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.A lubricant may be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances which swell when wetted to break up the tablet and releasethe compound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose,for example, may be used, as well as sodium lauryl sulfate. Also, superdisintegrants including, but not limited to, Ac-Di-Sol® (sodiumcroscarmellose cellulose), Explotab® (sodium starch glycolate),VivaStar® (sodium starch glycolate), and Polyplasdone disintegrants maybe used.

Tablets are often coated with sugar as a flavor and sealant. Thecompounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients. The size and shapeof the tablet may vary according to standard dimensions and shapes knownin the art.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders. The size and shape of the capsule may varyaccording to standard dimensions and shapes known in the art.

Furthermore, the capsule may be liquid-filled or non-liquid-filled. Thecapsule may be a hard or soft capsule. Furthermore, it may be a gelatincapsule, a starch capsule, a hydroxypropylmethylcellulose (HPMC)capsule, or a cellulosic capsule. Although not limited to capsules, suchdosage forms can further be coated with, for example, a seal coating, anenteric coating, an extended release coating, or a targeted delayedrelease coating. Additionally, liquid-filled capsules of the presentinvention may be emulsions and/or may contain tocopherol as a carrierfor poorly soluble compounds such as testosterone.

In one embodiment, the invention is directed to the use of tocopherol asthe hydrophobic dispersed phase of emulsions containing water insoluble,poorly water soluble therapeutic agents, water soluble ones which havebeen modified to be less water soluble, or mixtures thereof. In apreferred embodiment alpha-tocopherol is employed. Alpha-tocopherol issecreted by the enterocytes into the lymphatics and is processed in asimilar manner to other forms of vitamin E. Also called vitamin E,alpha-tocopherol is not a typical lipid oil. It has a higher polaritythan most lipid oils, particularly triglycerides, and is notsaponifiable. It has practically no solubility in water.

In an alternative embodiment, the invention is an alpha-tocopherolemulsion in the form of a self-emulsifying system where the system is tobe used for the oral administration of water-insoluble (or poorlywater-soluble or water-soluble agents modified to be less water solubleor mixtures thereof) drugs where that is desired. In this embodiment, anoil phase with surfactant and drug or drug mixture is encapsulated intoa soft or hard gelatin capsule. Suitable solidification agents withmelting points in the range of 40 to 60° C., such as high molecularweight polyethylene glycols (MW>1000), and glycerides, such as thoseavailable under the trade name Gelucire (Gattefose Corp., Saint Priest,France), can be added to allow filling of the formulation into a hardgelatin capsule at a high temperature. Semi-solid formulations areformed upon room temperature equilibration. Upon dissolution of thegelatin in the stomach and duodenum, the oil is released and forms afine emulsion with a mean droplet diameter of between about 1 to about15 microns, between about 2 to about 10 microns, or between about 2 toabout 5 microns spontaneously. The emulsion is then taken up by themicrovilli of the intestine and released into the bloodstream.

In an alternative embodiment, the invention comprises microemulsionscontaining tocopherol, preferably alpha-tocopherol. Microemulsions referto a sub-class of emulsions where the emulsion suspension is essentiallyclear and indefinitely stable by virtue of the extremely small size ofthe oil/drug microaggregates dispersed therein.

In another embodiment of the invention, PEGylated vitamin E(alpha-tocopheryl polyethylene glycol succinate, abbreviated TPGS) isused as a primary surfactant in emulsions of vitamin E. TPGS is utilizedas a primary surfactant, a stabilizer and also as a supplementarysolvent in emulsions of vitamin E. TPGS is a water-soluble derivative ofd-alpha-tocopheryl succinate. It is also used as an absorption andbioavailability enhancer for certain water-insoluble drugs (e.g. the HIVprotease inhibitor amprenavir) and fat-soluble vitamins such as vitaminD. TPGS, because of its amphipathic nature (has both hydrophilic andlipophilic ends), forms its own micelles and thus does not require bilesalts to do so. This makes it an excellent alpha-tocopherol substancefor those who have problems secreting bile salts into the intestine(e.g., those with chronic childhood cholestasis).

TPGS may enhance the absorption of lipophilic drugs if formulatedtogether with them. For this reason, the HIV protease inhibitoramprenavir is formulated with TPGS. Further, the enhancement of the oralbioavailability of some drugs when co-administered with TPGS may, inpart, be due to inhibition of P-glycoprotein in the intestine.P-glycoprotein is the multidrug resistance transporter and is involvedin the mediation of multidrug resistance.

In addition, polyethylene glycol (PEG) is also useful as a co-solvent inthe emulsions of this invention. Of particular use is polyethyleneglycol 200, 300, 400 or mixtures thereof.

The alpha-tocopherol concentration of the emulsions of this inventioncan be between about 1 to about 10% w/v, between about 2 to about 5%w/v, or between about 3 to about 4% w/v. The ratio of alpha-tocopherolto TPGS is optimally between about 1:1 to about 10:1 (w/w), betweenabout 1:1 to about 5:1 (w/w), or between about 1:1 to about 15:1 (w/w).

The emulsions of the invention may further include surfactants such asascorbyl-6 palmitate, stearylamine, PEGylated phospholipids, sucrosefatty acid esters and various vitamin E derivatives comprisingQ-tocopherol nicotinate, tocopherol phosphate, and nonionic, syntheticsurfactant mixtures, such as polyoxypropylene-polyoxyethylene glycolnonionic block copolymer.

The emulsions of the invention can comprise an aqueous medium. Theaqueous phase generally has an osmolality of approximately 300 mOsm andmay include sodium chloride, sorbitol, mannitol, polyethylene glycol,propylene glycol albumin, polypep and mixtures thereof. Osmolality mayalso range between about 100 to about 500 mOsm and between about 200 toabout 400 mOsm. This medium can also contain various additives to assistin stabilizing the emulsion or in rendering the formulationbiocompatible. Acceptable additives include acidifying agents,alkalizing agents, antimicrobial preservatives, antioxidants, bufferingagents, chelating agents, suspending and/or viscosity-increasing agents,and tonicity agents. Preferably, agents to control the pH, tonicity, andincrease viscosity are included. Optimally, a tonicity of at least 250mOsm is achieved with an agent which also increases viscosity, such assorbitol or sucrose. Tonicity may also be of at least 300 mOsm, at least400 mOsm, or at least 500 mOsm.

The emulsions of the invention for intravenous injection have a particlesize (mean droplet diameter) of about 10 to about 500 nm, preferablyabout 10 to about 200 nm and most preferably about 10 to about 100 nm.For intravenous emulsions, the spleen and liver will eliminate particlesgreater than 500 nm in size through the RES.

An embodiment of the invention includes testosterone within aliquid-capsule emulsion system.

Aqueous suspensions and/or elixirs are prepared by combining the activeingredient with various sweetening or flavoring agents, coloring matteror dyes, and, if so desired, emulsifying and/or suspending agents aswell, together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof. The amount of suspensionmay vary according to standard volumes known in the art.

Enteric formulations are often used to protect an active ingredient fromthe strongly acid contents of the stomach. Such formulations are createdby coating a solid dosage form with a film of a polymer which isinsoluble in acid environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate. It is preferred to formulateduloxetine and duloxetine-containing combinations as entericcompositions, and even more preferred to formulate them as entericpellets. The size and shape of such formulations may vary according tostandard dimensions and shapes known in the art.

Transdermal patches may also be used. Transdermal administrationsignificantly enhances patient compliance by alleviating the discomfortof needles and other dosage forms by providing a convenient dosage formfor once or twice weekly application. Such administration also providesthe benefit of having sustained blood levels of the drug beingadministered. Typically patches comprise a resinous composition in whichthe drugs will dissolve, or partially dissolve, which is held in contactwith the skin by a film which protects the composition. Other, morecomplicated patch compositions are also in use, particularly thosehaving a membrane pierced with innumerable pores through which the drugsare pumped by osmotic action. The size of the patch may vary accordingto sizes known in the art.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are also in wide use.

For parenteral, intradermal, intramuscular, or subcutaneousadministration pharmaceutical compositions may include one of thefollowing, or any combination thereof: a sterile diluent, such as water,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; surfactants such as polysorbate 80,sodium lauryl sulfate, sorbitan monopalmitate; alcohols; suspendingagent such as agar, bentonite, microcrystalline cellulose, sodiumcarboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth,veegum; antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; and buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose.

Pharmaceutical compositions can also include carriers to protect thecomposition against rapid degradation or elimination from the body, suchas a controlled release or sustained release or extended releaseformulation, including implants and microencapsulated delivery systems.For example, a time delay material such as glyceryl monostearate orglyceryl stearate alone, or in combination with a wax, may be employed.Also, pharmaceutical compositions can include excipients that modify gutmetabolism.

Additional methods of preparing various pharmaceutical compositions witha certain amount of each active ingredient are known, or will beapparent in light of this disclosure, to those skilled in this art.

The present invention is also directed to articles of manufacture suchas kits which include the active ingredients of the invention insuitable pharmaceutical compositions packaged for distribution. Kits ofthe invention can additionally include instructions for using the kitcomponents in a method of the invention. Instructions can includeinstructions for practicing any of the methods of the inventiondescribed herein. Thus, for example, a kit can include an androgenicagent or an aromatase inhibitor in a pharmaceutical formulation in acontainer, pack, or dispenser together with instructions foradministration to a human subject. Instructions may additionally includeindications of a satisfactory clinical endpoint or any adverse symptomsthat may occur, or any additional information required by the Food andDrug Administration for use in humans.

The instructions may be on “printed matter,” e.g., on paper or cardboardwithin the kit, or on a label affixed to the kit or packaging material,or attached to a vial or tube containing a component of the kit.Instructions may additionally be included on a computer readable medium,such as a disk (floppy diskette or hard disk), optical CD such as CD- orDVD-ROM/RAM, magnetic tape, electrical storage media such as RAM andROM, and hybrids of these such as magnetic/optical storage media.

Kits can additionally include a buffering agent, a preservative, or astabilizing agent. Each component of the kit can be enclosed within anindividual container and all of the various containers can be within asingle package.

Since the present invention relates to treatment with a combination ofthe two active ingredients which may be administered separately, theinvention also relates to combining separate pharmaceutical compositionsin kit form. The kit includes two separate pharmaceutical compositions:an androgenic agent and an aromatase inhibitor. The kit includes acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically thekit includes directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (e.g., tablets, capsules,and the like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It is desirable to provide a memory aid on a card insert, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be administered. Another example of such a memory aidis a calendar printed on the card. Other variations of memory aids willbe readily apparent.

Packaging can be accomplished by any of a number of means utilized inthe pharmaceutical industry. Examples of such packaging are: unit dosecontainers for dispensing liquid compositions enclosed in a box orcontainer along with package inserts; plastic and/or foil wrappersholding solid ocular inserts which contain the active ingredients of theinvention and which are enclosed in a box or container along withpackage inserts. Other modes of packaging would be readily apparent toone skilled in the pharmaceutical packaging arts.

The following example is included for purposes of illustration only andis not intended to limit the scope of the present invention, which isdefined by the appended claims. All references cited in the Example areincorporated herein by reference in their entireties.

EXAMPLE 1 Working

The following example demonstrates the advantages of administering to asubject diagnosed with breast cancer a pharmaceutical compositioncomprising an androgenic agent and an aromatase inhibitor.

Five post-menopausal women having similar patient socio-demographiccharacteristics and ranging in age from 49 years to 56 years (median age54) were selected for study. Each woman had been diagnosed withnode-negative estrogen receptor and PR (Progesterone Receptor) positiveBCa (Breast cancer), with tumor sizes ranging from 1.9 cm to 2.3 cm(median tumor size of 2.1 cm) and selected post-surgery (e.g.,mastectomy, lumpectomy, or quadrantectomy for primary breast cancer) andpost-chemotherapy. None had been subjected to previous attempts athormone replacement therapy.

Each woman selected was subjected to four weeks of aromatase inhibitortherapy (anastrozole 1 mg (ARIMIDEX®) orally as a tablet once a day),and thereafter to an additional eight weeks of the same aromataseinhibitor therapy in combination with the oral administration of 40 mgof testosterone undecanoate as a tablet once a day. During this study,side effects associated with aromatase inhibitor treatment were measuredat three separate times: prior to the first week of aromatase inhibitortherapy, following the fourth week of aromatase inhibitor therapy butbefore administration of testosterone undecanoate was begun, andfollowing the eighth week of combined aromatase inhibitor and androgenreplacement therapy. Measures of side effects were as follows: serumhormone levels, serum markers for bone resorption, serum lipid levels(see Haper-Wynne, et. al., Cancer Epidemiology, Biomakers & Prevention,Vol. 11, pp 614-621, July 2002, which is incorporated in its entiretyherein), FACT-ES side-effect profile evaluations, arthralgia (jointpain) evaluations, and cognitive function evaluations. Charts depictingthe results for these six measures as recorded at each of the threetimes are presented as FIG. 2 through FIG. 7. All result are the mean ofindividual scores with the bars representing standard error. Asdescribed hereafter, the novel therapies according to the presentinvention from this study demonstrate that androgen replacement therapyalleviates many of the side-effects of and/or enhances the efficacy ofaromatase inhibitor therapy in breast cancer treatment.

First, the chart in FIG. 2 demonstrates that testosterone aromatizationto estradiol is almost completely ablated during aromatase inhibitortherapy, thus validating that the methods according to the presentinvention do not elevate levels of estrogen appreciably in a manner thatcould result in increased risk of relapse of breast cancer. The y axisis picomoles/L of serum. As depicted in FIG. 2, following the fourthweek of aromatase inhibitor therapy (denoted by the “Al only” bars ) theaverage estradiol (denoted by “E2” in the figure legend) serum leveldrops significantly from the average level prior to the beginning ofaromatase inhibitor therapy (denoted “Pre-therapy”), while the remainderof the serum hormone levels appear relatively unchanged. After thesubsequent eight weeks of combination aromatase inhibitor and androgen(testosterone undecanoate) replacement therapy (denoted “Al+TU”), therewas only an insignificantly small increase in serum hormone levels ofestradiol while levels of testosterone (denoted by “T” in the figurelegend), free-testosterone (denoted by “FreeT” in the figure legend)and, in particular, dihydrotestosterone (denoted by “DHT” in the figurelegend) have shown notable increases;

Applicants believe that this increase in DHT is the cause of improvedpatient well being and health as described hereafter with reference toFIG. 3 through FIG. 6, as increases in tissue-specific DHT levels willresult in a reduction in the side-effects associated with aromataseinhibitors.

The chart depicted in FIG. 3 depicts the effects of combinationaromatase inhibitor (ARIMIDEX®) and androgenic agent (testosteroneundecanoate) upon the serum markers for bone resorption during thecourse of this study of post-menopausal patients. The y axis ispicomoles/L of serum. In particular, it is noted that measurements ofcarboxy-terminal collagen crosslinks (“CTx”) in serum in pmol/l for thepatients in the study showed that following eight weeks of combinationaromatase inhibitor and androgen replacement therapy, bone resorptionreturned to levels experienced prior to the beginning of aromataseinhibitor therapy. In fact, while not significantly large, there evenappeared to have been a small decrease in bone resorption relative tothe levels measured for the post-menopausal patients prior to thebeginning of any drug therapy. Measurements of carboxy-terminal collagencrosslinks were approximately 25% less in the Al+TU therapy than in thepre-therapy. Thus, the study supports the conclusion that androgenreplacement therapy according to the present invention couldcounterbalance the undesirable bone loss side-effects associated withextended therapy with aromatase inhibitors.

FIG. 4 is a chart demonstrating the effects of combination aromataseinhibitor (ARIMIDEX®) and androgenic agent (testosterone undecanoate) asmeasured by arthralgia evaluations in the post-menopausal patients inthis study. The y axis is a visual analogue pain scale. Specifically,the y axis indicates a percentage score of a subjective quantificationof pain measured out of 100.Again, the data regarding reportedarthralgia symptoms by the patients in the study showed that arthralgiareturned to pre-therapy levels after administration of testosteroneundecanoate was added to aromatase inhibitor therapy, as opposed toelevated levels of arthralgia that were reported during administrationof anastrozole only. Measurements of arthralgia were approximately 45%less in Al+TU therapy than in the pre-therapy.

At the three assessment times during the study, the quality of life foreach patient was assessed using standard Functional Assessment of CancerTherapy-Endocrine Symptoms (FACT-ES) questionnaire (See FIG. 8), whichquestionnaire is a standard method for determining the occurrence andprominence of treatment-related symptoms and side-effects in breastcancer patients. The y axis is a FACT-ES score. The total points fromthe FACT-ES questionnaire for each subject was subtracted from 200 toyield a FACT-ES score. A lower FACT-ES score, therefore, means the worsethe symptoms. Thus, a chart provided in FIG. 5 depicts the effect ofcombination aromatase inhibitor (ARIMIDEX®) and androgenic agent(testosterone undecanoate) as measured by FACT-ES side-effect profileevaluations at the three assessment times in this study, with a higherFACT-ES score being associated with an overall better quality of life.The data reported in FIG. 5 shows that quality of life as measured byFACT-ES questionnaires decreased upon the patients undergoing aromataseinhibitor-only therapy, but later improved to approximate pre-therapylevels upon the introduction of testosterone undecanoate administration.

With regard to the effect upon the cognitive function of the studypatients, the chart in FIG. 6 depicts the results measured by cognitivefunction evaluations in the patients at each of the three differentassessment times. The y axis is a mean Z score. The cognitive functionscores for the study patients in the pre-therapy evaluations, asexpected, varied slightly around scores for control populations in thefour different types of cognitive abilities that were tested, namelyprocessing speed, working memory, visual memory, and verbal memory. Asshown in FIG. 6, the cognitive function scores for the study patientsdecreased across all four ability types following the four weeks ofanastrozole-only therapy. Following the eight weeks of combinedaromatase inhibitor and testosterone undecanoate, however, the cognitivefunction scores improved across all four ability types enough torestore, or even possibly slightly improve, cognitive function in thestudy patients. Control was five age match healthy subjects.

Finally, the chart in FIG. 7 reports the data for the study patientscollected to monitor the effects of the combination aromatase inhibitorand testosterone undecanoate therapy upon serum lipid levels. The Y axisis mmol/L of serum. The results reported in the chart demonstrate thatthe combination therapy according to the present invention appears toraise no concerns regarding cholesterol.

EXAMPLES 2-13 Prophetic

The following examples demonstrate the advantages of administering to asubject diagnosed with breast cancer a pharmaceutical compositioncomprising an androgenic agent and/or an aromatase inhibitor, incombination or sequentially. It is to be understood that treatment ofthe patient with the disclosed products (both in these examples and inthe rest of the specification) can be start from the first day andcontinued for the appropriate time period to effectively treat thepatient without first administering the aromatase inhibitor by itselffor a period of time. It is contemplated that the treatment period wouldcontinued for about 3 months, for about 6 months, for about 1 year, forabout 2 years, for about 4 years or any longer or shorter time periodthat is deemed appropriate.

EXAMPLE 2 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 1 mg anastrozole (ARIMIDEX®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone undecanoate: 20 mg, 40 mg, or 80 mg once a day. Thecombination of anastrozole and testosterone undecanoate is administeredin a single dose capsule that has crystallized anastrozole andencapsulated testosterone undecanoate in an oil suspension. The sideeffects associated with anastrozole treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects. It is to be understood that the above treatment couldalso be start with the combination product from the first day andcontinued for the appropriate time period to effectively treat thepatient. It is contemplated that the treatment would be continued forabout 6 months to about four years or as long as is deemed appropriate.

EXAMPLE 3 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 25 mg exemestane (AROMASIN®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone undecanoate: 20 mg, 40 mg, or 80 mg once a day. Thecombination of exemestane and testosterone undecanoate is administeredin a single dose capsule that has crystallized exemestane andencapsulated testosterone undecanoate in an oil suspension. The sideeffects associated with exemestane treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects.

EXAMPLE 4 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 2.5 mg letrozole (FEMARA®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone undecanoate: 20 mg, 40 mg, or 80 mg once a day. Thecombination of letrozole and testosterone undecanoate is administered ina single dose capsule that has crystallized we need AZ comment hereletrozole and encapsulated testosterone undecanoate in an oilsuspension. The side effects associated with letrozole treatment aremeasured as described in Example 1. Data are expected to showimprovement of at least one or more side effects.

EXAMPLE 5 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 1 mg anastrozole (ARIMIDEX®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone: 20 mg, 40 mg, or 50 mg once a day. The combination ofanastrozole and testosterone is administered as a tablet and aninjection, a tablet and an a transdermal patch, a tablet andsubcutaneously, or a tablet and a capsule, respectively. The sideeffects associated with anastrozole treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects.

EXAMPLE 6 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 25 mg exemestane (AROMASIN®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone: 20 mg, 40 mg, or 50 mg once a day. The combination ofexemestane and testosterone is administered as a tablet and aninjection, a tablet and an a transdermal patch, a tablet andsubcutaneously, or a tablet and a capsule, respectively. The sideeffects associated with exemestane treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects.

EXAMPLE 7 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 2.5 mg letrozole (FEMARA®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone: 20 mg, 40 mg, or 50 mg once a day. The combination ofletrozole and testosterone is administered as a tablet and an injection,a tablet and an a transdermal patch, a tablet and subcutaneously, or atablet and a capsule, respectively. The side effects associated withletrozole treatment are measured as described in Example 1. Data areexpected to show improvement of at least one or more side effects.

EXAMPLE 8 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 1 mg anastrozole (ARIMIDEX®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts ofmethyltestosterone: 0.5 mg, 1.25 mg, or 2.5 mg once a day. Thecombination of anastrozole and methyltestosterone is administered in asingle dose tablet. The side effects associated with anastrozoletreatment are measured as described in Example 1. Data are expected toshow improvement of at least one or more side effects.

EXAMPLE 9 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 25 mg exemestane (AROMASIN®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts ofmethlytestosterone: 0.5 mg, 1.25 mg, or 2.5 mg once a day. Thecombination of exemestane and methyltestosterone is administered in asingle dose tablet. The side effects associated with exemestanetreatment are measured as described in Example 1. Data are expected toshow improvement of at least one or more side effects.

EXAMPLE 10 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 2.5 mg letrozole (FEMARA®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts ofmethyltestosterone: 0.5 mg, 1.25 mg, or 2.5 mg once a day. Thecombination of letrozole and methyltestosterone is administered in asingle dose tablet. The side effects associated with letrzole treatmentare measured as described in Example 1. Data are expected to showimprovement of at least one or more side effects.

EXAMPLE 11 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 1 mg anastrozole (ARIMIDEX®)) orally as a tablet once aday, and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone propionate: 20 mg, 40 mg, or 80 mg once a day. oral Thecombination of anastrozola and testosterone undecanoate is administeredin a single dose capsule that has crystallized anastrozole andencapsulated testosterone undecanoate in an oil suspension. The sideeffects associated with anastrozole treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects.

EXAMPLE 12 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 25 mg exemestane (AROMASIN®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone propionate: 20 mg, 40 mg, or 80 mg once a day oral. Thecombination of exemestane and testosterone undecanoate is administeredin a single dose capsule that has crystallized exemestane andencapsulated testosterone undecanoate in an oil suspension. The sideeffects associated with exemestane treatment are measured as describedin Example 1. Data are expected to show improvement of at least one ormore side effects.

EXAMPLE 13 Prophetic

Each woman selected is subjected to four weeks of aromatase inhibitortherapy with 2.5 mg letrozole (FEMARA®) orally as a tablet once a day,and thereafter to an additional eight weeks of the same aromataseinhibitor in combination with at least one of the following amounts oftestosterone propionate: 20 mg, 40 mg, or 80 mg once a day. Thecombination of letrozole and testosterone undecanoate is administered ina single dose capsule that has crystallized letrozole and encapsulatedtestosterone undecanoate in an oil suspension. The side effectsassociated with letrozole-treatment are measured as described inExample 1. Data are expected to show improvement of at least one or moreside effects.

Pharmaceutical compositions according to this invention generally willbe administered in a convenient formulation. The following formulationexamples only are illustrative and are not intended to limit the scopeof the present invention.

While the present invention has been described in terms of preferredembodiments in order to facilitate better understanding of theinvention, it should be appreciated that various modifications can bemade without departing from the principles of the invention. Therefore,the invention should be understood to include all such modificationswithin its scope. Numerous insubstantial variations, changes, andsubstitutions will now be apparent to those skilled in the art withoutdeparting from the scope of the invention disclosed herein. Accordingly,it is intended that the invention be limited only by the spirit andscope of the claims as will be allowed.

1. A pharmaceutical composition for improving one or more side effectsassociated with aromatase inhibitor treatment in a subject diagnosedwith breast cancer, said pharmaceutical composition comprising (a) aneffective amount of an androgenic agent and (b) an effective amount ofan aromatase inhibitor, and optionally a pharmaceutically acceptableexcipient and/or carrier.
 2. A pharmaceutical composition according toclaim 1, wherein the androgenic agent is selected from the groupconsisting of: testosterone, methyitestosterone, androstenediol,androstenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione, adrenosterone,androsterone acetate, androsterone propionate, androsterone benzoate,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,oxymetholone, fluoxymesterone, methandrostenolone, testolactone,pregnenolone, 17α-methylnortestosterone, norethandrolone,dihydrotestosterone, 5α-dihydrotestosterone, dromostanolone,dromostanolone propionate, nandrolone, nandrolone phenpropionate,nandrolone decanoate, nandrolone furylpropionate, nandrolonecyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, danazol, oxymetholone, androsterone, stanozolol,ethylestrenol, oxandrolone, bolasterone, mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate,testosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosteroneundecanoate, testosterone caprate, testosterone isocaprate, and isomers,metabolites, derivatives, and precursors of any of the aforementionedcompounds, and combinations thereof.
 3. A pharmaceutical compositionaccording to claim 2, wherein the androgenic agent is testosterone.
 4. Apharmaceutical composition according to claim 2, wherein the androgenicagent is testosterone undecanoate.
 5. A pharmaceutical compositionaccording to claim 4, wherein the effective amount is about 40 mg perday.
 6. A pharmaceutical composition according to claim 2 wherein theandrogenic agent is methyltestosterone.
 7. A pharmaceutical compositionaccording to claim 2, wherein the androgenic agent is DHT.
 8. Apharmaceutical composition according to claim 1, wherein the aromataseinhibitor is a steroidal aromatase inhibitor, or an isomer thereof.
 9. Apharmaceutical composition according to claim 1, wherein the steroidalaromatase inhibitor is selected from a group consisting of exemestane orformestane.
 10. A pharmaceutical composition according to claim 1,wherein the aromatase inhibitor is a nonsteroidal aromatase inhibitor,or an isomer thereof.
 11. A pharmaceutical composition according toclaim 1, wherein the nonsteroidal aromatase inhibitor is selected from agroup consisting of anastrozole, letrozole, vorozole or fadrozole.
 12. Apharmaceutical composition according to claim 11, wherein thenonsteroidal aromatase inhibitor is anastrozole.
 13. A pharmaceuticalcomposition according to claim 12, wherein the effective amount is about1 mg per day.
 14. A pharmaceutical composition according to claim 1,comprising (a) testosterone undecanoate, wherein the effective amount isabout 40 mg, and (b) anastrozole, wherein the effective amount is about1 mg.
 15. A pharmaceutical composition according to claim 1, wherein theside effects. Comprise: vasodilatation, osteoporosis, osteopenia, lossof libido, weight gain, vaginal dryness, sleeping difficulties, nightsweats, asthenia, painful intercourse, pain, arthritis, arthralgia,breast pain, pharyngitis, depression, bloating, nausea, rash, moodswings, headache, hypertension, insomnia, lymphoedema, back pain,peripheral edema, cold sweats, abdominal pain, injury, constipation,coughing, diarrhea, fracture, hypercholesteremia, infection, arthrosis,dizziness, dyspnea, paresthesia, urinary tract infection,vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia, flu syndrome,gastrointestinal disorder, sweating and leukorrhea.
 16. A pharmaceuticalcomposition for improving one or more side effects associated witharomatase inhibitor treatment in a subject diagnosed with breast cancer,said pharmaceutical composition comprising an effective amount of anandrogenic agent, and optionally a pharmaceutically acceptable excipientand/or carrier.
 17. A pharmaceutical composition according to claim 16,wherein the androgenic agent is selected from the group consisting of:testosterone, methyltestosterone, androstenediol,androstenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione, adrenosterone,androsterone acetate, androsterone propionate, androsterone benzoate,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,oxymetholone, fluoxymesterone, methandrostenolone, testolactone,pregnenolone, 17α-methylnortestosterone, norethandrolone,dihydrotestosterone, 5α-dihydrotestosterone, dromostanolone,dromostanolone propionate, nandrolone, nandrolone phenpropionate,nandrolone decanoate, nandrolone furylpropionate, nandrolonecyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, danazol, oxymetholone, androsterone, stanozolol,ethylestrenol, oxandrolone, bolasterone, mesterolone, testosteronepropionate, testosterone cypionate, testosterone phenylacetate,testosterone enanthate, testosterone acetate, testosterone buciclate,testosterone heptanoate, testosterone decanoate, testosteroneundecanoate, testosterone caprate, testosterone isocaprate, and isomers,metabolites, derivatives, and precursors of any of the aforementionedcompounds, and combinations thereof.
 18. A pharmaceutical compositionaccording to claim 17, wherein the androgenic agent is testosterone. 19.A pharmaceutical composition according to claim 18, wherein theandrogenic agent is testosterone undecanoate.
 20. A pharmaceuticalcomposition according to claim 19, wherein the effective amount is about40 mg per day.
 21. A pharmaceutical composition according to claim 17wherein the androgenic agent is methyltestosterone.
 22. A pharmaceuticalcomposition according to claim 17, wherein the androgenic agent is DHT.23. A pharmaceutical composition according to claim 16, wherein the sideeffects comprise: vasodilatation, osteoporosis, osteopenia, loss oflibido, weight gain, vaginal dryness, sleeping difficulties, nightsweats, asthenia, painful intercourse, pain, arthritis, arthralgia,breast pain, pharyngitis, depression, bloating, nausea, rash, moodswings, headache, hypertension, insomnia, lymphoedema, back pain,peripheral edema, cold sweats, abdominal pain, injury, constipation,coughing, diarrhea, fracture, hypercholesteremia, infection, arthrosis,dizziness, dyspnea, paraesthesia, urinary tract infection,vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia, flu syndrome,gastrointestinal disorder, sweating and leukorrhea.
 24. A method forimproving one or more side effects associated with aromatase inhibitortreatment in a subject diagnosed with breast cancer, said methodcomprising administering to said subject a pharmaceutical compositionaccording to claim
 1. 25. A method according to claim 24, wherein eitheror both the androgenic agent and the aromatase inhibitor areadministered orally, intraperitoneally, intradermally, transdermally,transmucosally, subcutaneously, sublingually, intravenously,intraarterially, intracavity, intracranially, intramuscularly,parenterally, or topically, or a combination thereof.
 26. A methodaccording to claim 25, wherein said pharmaceutical composition isadministered orally.
 27. A method according to claim 26, wherein saidpharmaceutical composition is administered as a tablet.
 28. A methodaccording to claim 27, wherein said tablet is administered once a day.29. A method according to claim 24, wherein the side effects comprise:vasodilatation, osteoporosis, osteopenia, loss of libido, weight gain,vaginal dryness, sleeping difficulties, night sweats, asthenia, painfulintercourse, pain, arthritis, arthralgia, breast pain, pharyngitis,depression, bloating, nausea, rash, mood swings, headache, hypertension,insomnia, lymphoedema, back pain, peripheral edema, cold sweats,abdominal pain, injury, constipation, coughing, diarrhea, fracture,hypercholesteremia, infection, arthrosis, dizziness, dyspnea,paraesthesia, urinary tract infection, vulvovaginitis, anxiety, bonepain, chest pain, dyspepsia, flu syndrome, gastrointestinal disorder,sweating and leukorrhea.
 30. A method according to claim 24, whereinsaid subject is a postmenopausal woman.
 31. A method for improving thehealth of a subject with breast cancer wherein said subject has sideeffects associated with aromatase inhibitor treatment, comprisingadministering a pharmaceutical composition according to claim
 1. 32. Amethod according to claim 31, wherein either or both the androgenicagent and the aromatase inhibitor are administered orally,intraperitoneally, intradermally, transdermally, transmucosally,subcutaneously, sublingually, intravenously, intraarterially,intracavity, intracranially, intramuscularly, parenterally, ortopically, or a combination thereof.
 33. A method according to claim 32,wherein said pharmaceutical composition is administered orally.
 34. Amethod according to claim 33, wherein said pharmaceutical composition isadministered as a tablet.
 35. A method according to claim 34, whereinsaid tablet is administered once a day.
 36. A method according to claim31, wherein the side effects comprise: vasodilatation, osteoporosis,osteopenia, loss of libido, weight gain, vaginal dryness, sleepingdifficulties, night sweats, asthenia, painful intercourse, pain,arthritis, arthralgia, breast pain, pharyngitis, depression, bloating,nausea, rash, mood swings, headache, hypertension, insomnia,lymphoedema, back pain, peripheral edema, cold sweats, abdominal pain,injury, constipation, coughing, diarrhea, fracture, hypercholesteremia,infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary tractinfection, vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia,flu syndrome, gastrointestinal disorder, sweating and leukorrhea.
 37. Amethod according to claim 31, wherein said subject is a postmenopausalwoman.
 38. A method for manufacturing a pharmaceutical compositionaccording to claim 1, comprising selecting an androgenic agent.
 39. Amethod according to claim 38, further comprising adding an aromataseinhibitor.
 40. A kit for improving one or more side effects associatedwith aromatase inhibitor treatment in a subject diagnosed with breastcancer, comprising (a) an androgenic agent and (b) an aromataseinhibitor, and, optionally, instructions for administration of compounds(a) and (b).
 41. A kit according to claim 40, wherein the androgenicagent is selected from the group consisting of testosterone,methyltestosterone, androstenediol, androstenediol-3-acetate,androstenediol-17-acetate, androstenediol-3,17-diacetate,androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,androstenedione, adrenosterone, androsterone acetate, androsteronepropionate, androsterone benzoate, dehydroepiandrosterone, sodiumdehydroepiandrosterone sulfate, oxymetholone, fluoxymesterone,methandrostenolone, testolactone, pregnenolone,17α-methylnortestosterone, norethandrolone, dihydrotestosterone,5α-dihydrotestosterone, dromostanolone, dromostanolone propionate,nandrolone, nandrolone phenpropionate, nandrolone decanoate, nandrolonefurylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate,nandrolone cyclohexanecarboxylate, danazol, oxymetholone, androsterone,stanozolol, ethylestrenol, oxandrolone, bolasterone, mesterolone,testosterone propionate, testosterone cypionate, testosteronephenylacetate, testosterone enanthate, testosterone acetate,testosterone buciclate, testosterone heptanoate, testosterone decanoate,testosterone undecanoate, testosterone caprate, testosterone isocaprate,and isomers, metabolites, derivatives, and precursors of any of theaforementioned compounds, and combinations thereof.
 42. A kit accordingto claim 41, wherein the androgenic agent is testosterone.
 43. A kitaccording to claim 42, wherein the androgenic agent is testosteroneundecanoate.
 44. A kit according to claim 42, wherein the androgenicagent is methyltestosterone.
 45. A kit according to claim 42, whereinthe androgenic agent is DHT.
 46. A kit according to claim 40, whereinthe aromatase inhibitor is a steroidal aromatase inhibitor, or an isomerthereof.
 47. A kit according to claim 46, wherein the steroidalaromatase inhibitor is selected from a group consisting of exemestane orformestane.
 48. A kit according to claim 40, wherein the aromataseinhibitor is a nonsteroidal aromatase inhibitor, or an isomer thereof.49. A kit according to claim 48, wherein the nonsteroidal aromataseinhibitor is selected from a group consisting of anastrozole, letrozole,vorozole or fadrozole.
 50. A kit according to claim 49, wherein thenonsteroidal aromatase inhibitor is anastrozole.
 51. A kit according toclaim 40, wherein the side effects comprise: vasodilatation,osteoporosis, osteopenia, loss of libido, weight gain, vaginal dryness,sleeping difficulties, night sweats, asthenia, painful intercourse,pain, arthritis, arthralgia, breast pain, pharyngitis, depression,bloating, nausea, rash, mood swings, headache, hypertension, insomnia,lymphoedema, back pain, peripheral edema, cold sweats, abdominal pain,injury, constipation, coughing, diarrhea, fracture, hypercholesteremia,infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary tractinfection, vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia,flu syndrome, gastrointestinal disorder, sweating and/or leukorrhea. 52.A pharmaceutical composition according to claim 1, wherein saidaromatase inhibitor treatment is an adjuvant therapy treatment to saidsubject already having received chemotherapy.
 53. A method according toclaim 24, wherein said aromatase inhibitor treatment is an adjuvanttherapy treatment to said subject already having received chemotherapy.54. A method according to claim 31, wherein said aromatase inhibitortreatment is an adjuvant therapy treatment to said subject alreadyhaving received chemotherapy.
 55. A method for enhancing the efficacy ofaromatase inhibitors comprising administering a pharmaceuticalcomposition according to claim
 1. 56. A pharmaceutical composition forimproving one or more side effects associated with aromatase inhibitortreatment in a subject diagnosed with breast cancer comprising (a) aneffective amount of an androgenic agent, and (b) an effective amount ofan agent that blocks conversion of testosterone to estradiol.
 57. Amethod for improving one or more side effects associated with aromataseinhibitor treatment in a subject diagnosed with breast cancer, saidmethod comprising administering a pharmaceutical composition accordingto claim
 56. 58. A method for increasing the bioavailability of anandrogenic agent comprising administering a pharmaceutical compositionaccording claim
 1. 59. A method according to claim 52, wherein saidandrogenic agent is testosterone.
 60. A method according to claim 53,wherein said aromatase inhibitor is anastrozole.
 61. A method accordingto claim 53, wherein said aromatase inhibitor blocks conversion of saidtestosterone to estrogen.
 62. A method according to claim 55, whereinsaid conversion is blocked in small bowel lymphatics and liver.